Abstract: FR-PO354

Myeloid TGFβ Receptor Promotes Fibrosis after AKI

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Zhang, Ming-Zhi, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Overstreet, Jessica Marie, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Wang, Yinqiu, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Niu, Aolei, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Wang, Suwan, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Gewin, Leslie S., Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Harris, Raymond C., Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background

Transforming growth factor-β (TGF-β) is a central mediator of fibrosis. TGF-β signals through a receptor complex composed of two type I and two type II transmembrane subunits. Renal macrophages are major producers of TGF-β1 and play important roles in the development of fibrosis after acute kidney injury (AKI). However, a previous study found that deletion of myeloid TGF-β1 did not prevent fibrosis after severe renal ischemia/reperfusion (I/R) or obstructive injury. In the present study we examined whether deletion of myeloid type II TGF-ß receptors (Tgfbr2) affected development of fibrosis after AKI.

Methods

Wild type (Tgfbr2f/f) or KO (CD11b-Cre;Tgfbr2f/f or LysM-Cre;Tgfbr2f/f) mice (male, 3 months old, C57BL/6) were used. For a severe I/R AKI model, the animals were uninephrectomized, immediately followed by unilateral I/R with renal pedicle clamping for 29 min. Mice were sacrificed after 3 weeks. For an AKI-chronic kidney disease (CKD) model, unilateral I/R with renal pedicle clamping for 31 min was performed, with contralateral uninephrectomy on the 8th day, and animal sacrifice on day 28.

Results

Deletion of macrophage/dendritic cell Tgfbr2 did not affect functional recovery from AKI, as indicated by similar rates of BUN and creatinine recovery. However, deletion of Tgfbr2 in macrophages/dendritic cells led to dramatic decreases in development of fibrosis at 3 weeks in the severe AKI model, as indicated by quantitative picro-sirius red staining and Masson’s trichrome staining. Deletion of Tgfbr2 in macrophages/dendritic cells was associated with decreased expression levels of profibrotic and fibrotic components, including CTGF, α-SMA and collagen I. In addition, macrophage/dendritic cell Tgfbr2 deletion led to marked decreases in macrophage and T cell infiltration and oxidative stress. Macrophage/dendritic cell Tgfbr2 deletion also markedly reduced development of fibrosis in the AKI-CKD model. In renal macrophages/dendritic cells isolated with CD11b microbeads, Tgfbr2 deletion led to decreased expression levels of M2 markers and increased M1 markers.

Conclusion

These studies indicate that myeloid Tgfbr2 promotes fibrosis after severe AKI at least in part by promotion of M2 polarization and suggest that activation of myeloid TGF-β receptors by TGF-β produced by non-myeloid cell types plays an important role in this process.

Funding

  • NIDDK Support